The goal of this renewal application is to provide continued support for my mentoring program for junior faculty and fellows interested in patient- oriented research (POR). During my first K24, 2 junior faculty completed K awards, one received an R01 and 4 were awarded new K23s, a highly successful record. My future research goals are to conduct high quality POR elucidating cellular and structural mechanisms that underlie deficits in bone strength associated with postmenopausal osteoporosis, idiopathic osteoporosis (IOP) in premenopausal women, and other diseases associated with adverse effects on the skeleton. My mentoring goals are to use currently and newly funded projects to provide high quality mentoring and training for new clinical investigators in POR. During the grant, we defined consistent microarchitectural abnormalities of bone quality in women with IOP: thin cortices, trabecular loss, decreased connectivity, stiffness and mineralization. Despite some heterogeneity, the majority had low or normal remodeling. In the renewal, we will test the hypotheses that microarchitectural abnormalities in premenopausal women with IOP are related to abnormal formation, function or lifespan of bone cells, particularly osteoblasts and that PTH(1-34), a bone anabolic agent, can reverse the structural and dynamic abnormalities we have defined. We will use established and novel approaches to skeletal macro- and micro-imaging and cell biology that will provide novel insights into mechanisms of bone loss in IOP and a rational basis for its therapy. This proposal, as well as databases, biological specimens and imaging data from other currently and newly funded projects, will provide me with many opportunities to mentor junior investigators in POR and will also provide me with protected time to focus on training and mentoring. By investigating the causes and therapy of IOP, improving the health of young women with unexplained fractures, and permitting me to devote more time to POR and to training and mentoring junior faculty and fellows in POR, this proposal addresses several key missions of NIH.